In situ electrochemical nanoindentation (ECNI) has been used to study the effect of hydrogen on Fe-22Mn-0.6C TWIP steel at different potentials. Two grains with different orientations have been tested in this study. The pop-in load, pop-in width and nano-hardness data were extracted and analyzed. It is clearly shown that pop-in load and width were reduced while hardness was increased by charged hydrogen for both grains. Higher cathodic potential causes higher hydrogen concentration leading to a more obvious change of nanomechanical properties. It is proposed that the homogeneous dislocation nucleation (HDN) was reduced and dislocation mobility was limited by the dissolved hydrogen. In addition, the results also show that (110) grain has a higher hydrogen sensitivity than (100) grain.